Patients suffering from diabetes occasionally develop diabetic retinopathy, the leading cause of blindness of people aged 20-60.
Diabetic retinopathy is a non-degenerative disease of the small blood vessels of the retina, which is the light-sensitive tissue in the back of the eye. Diabetic retinopathy is related to the abnormally elevated levels of blood sugar in diabetes, and the retinal changes include impaired vascular function, vascular leakage, vascular congestion, vascular occlusion, tissue swelling (edema) and tissue ischemia. Metabolic hyperactivity and hyperfusion are also implicated in the development of diabetic retinopathy.
The lower grades of diabetic retinopathy are collectively called diabetic background retinopathy or nonproliferative diabetic retinopathy. Leakage of fluid from diseased retinal vessels may cause swelling of the center of the retina (the foeva, which is in the center of the macula) and hence cause blurred vision and severe visual loss secondary to diabetic macular edema. Reduced retinal perfusion secondary to microvascular occlusion may cause the growth of new vessels from intact vessel. Such neovascularizations (proliferative diabetic retinopathy) may cause preretinal hemorrhage, traction detachment of the retina, and severe visual loss. About half of the people with proliferative retinopathy also experience macular edema, which can occur at any stage of diabetic retinopathy.
The conventional primary means of treating diabetic retinopathy target its macular edema and proliferative retinopathy stages. The treatment consists of producing multiple circumscribed photocoagulation lesions of the outer layers of the retina, using, for instance, blue-green 514.5 nm light from an argon ion laser. Such lesions induce focal necrosis and permanent functional loss, but if applied properly, the treatment may result in improved preservation of some visual function rather than complete or incapacitating visual loss. The function of the center of the visual field is given special priority. The mechanism of action of photocoagulation treatment involves reduction of oxygen demand by removal of a large proportion of the retinal photoreceptors and enhanced drainage of fluid from the retina to the choroid, and probably also perfusion reduction.
If severe preretinal bleeding or traction from fibrotic proliferations occur, surgical removal of blood, fibrous tissue, and vitreous gel can be performed. Vitrectomy is usually accompanied by retinal photocoagulation treatment if this has not been completed on beforehand. Overall, photocoagulation and vitrectomy are successful only in reducing the rate of visual loss in patients with diabetic retinopathy to about half of the spontaneous rate. Photocoagulation has considerable drawbacks, because it is only moderately effective and because it invariably induces loss of vision corresponding to the location of the coagulation injury.
Once a patient has been diagnosed with diabetic retinopathy the risk of bleeding will always be present and repeated treatment may be needed. Diabetic retinopathy has no early warning signs and macular edema and proliferative diabetic retinopathy can develop without any premonitory symptoms, therefore diabetic retinopathy may develop undetected to the severe stages of the disease.
Currently, besides attempting to control levels of blood sugar, blood pressure and blood cholesterol, no method for prevention of diabetic retinopathy is known. A preventive mode of treatment would substantially reduce occurrence of eyesight loss in diabetic patients and ease the course of the disease. Furthermore, a modality of treatment that is better than conventional treatment or an effective adjunct to conventional treatment will be of considerable benefit to patients with diabetes.
Retinoids are a class of compounds with several functional activities consisting of four isoprenoid units joined in a head-to-tail manner (9). Several such compounds are vitamins or provitamins because they possess the biological activity of vitamin A, which is not synthesized in the body and must be derived from the diet. Retinoids are also hormones with intracrine activity and capable of binding to nuclear receptors resulting in the alteration of cell division and immune function.
The visual response in vertebrates begins by a light-induced isomerisation of the rhodopsin chromophore, 11-cis-retinal, in the photoreceptor cells of the retina. Light bleaches 11-cis-retinal to all-trans-retinol (vitamin A), which cannot be synthesized de novo by mammals. The bleaching of the purple-red rhodopsin to visual yellow initiates retinal visual signalling. The recovery mechanism from bleach requires reconversion of the chromophore to 11-cis-retinal by a multiple of enzymatic reactions called the visual cycle (FIGS. 1, 2 and 3). This process takes place in the retinal pigment epithelium (RPE), a cell layer lying adjacent to the photoreceptor cells (1).
The colour and sensitivity to light of the rhodopsin protein in the photoreceptors depend upon the presence of 11-cis-retinal. Disruption of the visual cycle retards restoration of the visual function after exposure to bright light. Notably dark adaptation and night vision are deficient in subjects with deficient uptake of vitamin A (2). Night blindness can also be induced by dietary substitution of vitamin A with retinoic acid in rats (3).
The retinoids comprise a group of natural and synthetic compounds with structural similarities and affinity for biological receptors for vitamin A (retinol). Retinoids possess dual functional activities as hormones and vitamins, respectively. They stimulate nuclear retinoid receptors controlling cell division and immune function, and they absorb photons in the retina and then initiate the visual (vitamin A) cycle.
A synthetic analogue of vitamin A, the retinoid isotretinoin (13-cis-retinoic acid), is commonly used for treatment of severe nodular acne and various other skin disorders for almost two decades. Known side-effects of isotretinoin treatment are night blindness and excessive glare sensitivity (4-6) and experiments have shown that isotretinoin exerts its effect by inhibiting the processing of vitamin A in the retina and the RPE (7-8). Other retinoids, such as the 11-cis-retinoids have been shown to inhibit enzymes involved in catalyzing processes of the visual cycle and thereby slow dark adaptation in treated subjects (13).
During dark adaptation, the photoreceptor layer removes considerable amounts of oxygen from the inner retina leading to an unusually low oxygen tension. Retinal hypoxia has been shown to play a major role in the development of diabetic retinopathy and elimination of periods with full dark adaptation by low levels of background light at night has been suggested as a therapeutic against diabetic retinopathy (14).